TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis

Abstract

BackgroundNeurocysticercosis (NCC) is an infection of the brain with the larval cyst of the tapeworm, Taenia solium. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN), an anti-tumor necrosis factor agent, or dexamethasone (DEX), a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ).Methodology/Principal findingsWe followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9), pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6), and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6). The fourth group remained untreated (n = 3). As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB) (a measure of blood brain barrier dysfunction) compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA)4, interleukin (IL)-13 and transforming growth factor (TGF)-β; the tissue remodeling genes matrix metalloprotease (MMP)1 and 9, tissue inhibitors of metalloproteases (TIMP)1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF)1, angiopoietin (Ang)1, Ang 2, and platelet endothelial cell adhesion molecule (PECAM)-1. In contrast, transcription was only modestly decreased in the DEX pretreated pigs compared to PZQ alone, and only for TNF-α, IL-6, IFN-γ, TGF-β and Ang1. IL-10 was not affected by either ETN or DEX pretreatments. The degree of inflammation, assessed by semi-quantitative inflammatory scores, was modestly decreased in both ETN and DEX pretreated animals compared to PZQ treated pigs whereas cyst damage scores were moderately decreased only in cysts from DEX pretreated pigs. However, the proportion of cysts with EB extravasation was not significantly changed in ETN and DEX pretreated groups.Conclusions/SignificanceOverall, TNF-α blockade using ETN treatment modulated expression of a large variety of genes that play a role in induction and control of inflammation and structural changes. In contrast the number of inflammatory cells was only moderately decreased suggesting weaker effects on cell migration into the inflammatory capsules surrounding cysts than on release of modu...

Clinicopathology conference: 41‐year‐old woman with chronic relapsing meningitis

“…67 On this therapy, she tolerated a steroid taper for the first time in 2 years, and after a year was able to discontinue steroids completely. She was also started on the tumor necrosis factor α inhibitor etanercept to protect against an inflammatory reaction to degenerating cysts.…”

Granulomatous responses in larval taeniid infections

“…TNF‐α is expressed at the mRNA levels in some granuloma macrophages in human AE . TNF‐α is also expressed in periparasitic tissue in natural pig T. solium infections in brain and muscle; levels are highest around degenerative metacestodes, as are those of other proinflammatory cytokines (IL‐1β, IL‐6, IL‐8) . TNF‐α contributes to post‐parasite death inflammation in pig brain cysticercosis, as attested by experiments with TNF‐α blockade at the time of pharmacological disruption of parasites …”

“…The third point is clear from observations in all systems discussed, and it is probably underpinned by a bidirectional relationship: inflammation causes parasite death, and parasite death causes inflammation. Inflammatory exacerbation following parasite death is a well‐documented phenomenon in NCC and pig models of NCC, including the context of anti‐helminthic pharmacological intervention . Such inflammation is surely the combined result of release of sequestered parasite molecules that constitute danger signals for innate immunity and the discontinuation of parasite‐derived anti‐inflammatory signals.…”

“…Inflammatory exacerbation following parasite death is a well-documented phenomenon in NCC and pig models of NCC, including the context of anti-helminthic pharmacological intervention. 29,102 Such inflammation is surely the combined result of release of sequestered parasite molecules that constitute danger signals for innate immunity and the discontinuation of parasite-derived anti-inflammatory signals. The evidence for parasite destruction by granulomatous inflammation will be discussed in the following section.…”

“…104 TNFα is also expressed in periparasitic tissue in natural pig T. solium infections in brain and muscle; levels are highest around degenerative metacestodes, as are those of other proinflammatory cytokines (IL-1β, IL-6, IL-8). 102,105 TNFα contributes to post-parasite death inflammation in pig brain cysticercosis, as attested by experiments with TNFα blockade at the time of pharmacological disruption of parasites. 102 The limited evidence available suggests that T cells, and αβ + CD4 + cells in particular, are necessary for granulomatous responses to larval taeniids, as may be expected.…”